SURVEILLANCE REPORT. Antimicrobial resistance surveillance in Europe.

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1 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe

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3 Antimicrobial resistance surveillance in Europe Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2010

4 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT Coordination This report of the European Centre for Disease Prevention and Control (ECDC) was coordinated by Ole Heuer. Contributing authors Ole Heuer, Anna-Pelagia Magiorakos, Marianne Gunell, Assimoula Economopoulou, Paula Bianca Blomquist, Derek Brown, Christine Walton, Nita Patel and Dominique Monnet. Data analysis Carlo Gagliotti, Carl Suetens, Jolanta Griskeviciene Acknowledgements The EARS-Net Coordination group members: Christian Giske, Hajo Grundmann, Vincent Jarlier, Gunnar Kahlmeter, Jolanta Miciuleviciene, Gian Maria Rossolini, Gunnar Skov Simonsen, Nienke van de Sande- Bruinsma and Helena Zemlickova are acknowledged for providing valuable comments and scientific advice during the production of the report. All EARS-Net participants and National Epidemiological Contact Points are acknowledged for providing valuable comments for this report. All EARS-Net participating laboratories and hospitals in the Member States are acknowledged for providing data for this report. John Stelling, Silvia Sarbu and Catalin Albu are acknowledged for data management and providing helpdesk support to the participating countries. Revised December 2011 This edition has been revised to correct a number of errors. The changes affect Figures 5.31 (Estonia and Romania), 5.32 (Estonia), 5.33 (Estonia and Romania) and 5.34 (Estonia). Estonia has been added to the listed countries showing a decrease in MRSA: pages 1, 30. Greece has been added as showing a significant decrease in vancomycin-resistant E faecium: page 34. Table 5.8a has been added. Suggested citation for full report: European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; Cover picture istockphoto ISSN ISBN doi /14911 European Centre for Disease Prevention and Control, Reproduction is authorised, provided the source is acknowledged. ii

5 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe 2010 Contents Abbreviations and acronyms vii Countries participating in EARS-Net ix National institutions/organisations participating in EARS-Net xi Summary Introduction Carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa. Analysis of data from laboratories reporting continuously from 2005 to Introduction Methods Results Discussion External Quality Assessment Exercise (EQA) Introduction Results Conclusions EARS-Net laboratory/hospital denominator data Introduction Methods Participation Population coverage Hospital denominator information Hospital characteristics Laboratory denominator information Conclusions Antimicrobial resistance in Europe Streptococcus pneumoniae Staphylococcus aureus Enterococci Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Annex 1: Technical notes Annex 2: Country summary sheets iii

6 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT List of tables 2.1: Numbers of laboratories reporting continuously and average numbers of K. pneumoniae and P. aeruginosa isolates reported per country per year to EARSS/EARS-Net during : Klebsiella pneumoniae (0243): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Escherichia coli (0244): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Streptococcus pneumoniae (0245): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Enterococcus faecium (0246): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Pseudomonas aeruginosa (0247): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Staphylococcus aureus (0248): Minimum inhibitory concentration (MIC) and intended results reported by the reference laboratories and the overall concordance of the participating laboratories : Hospital denominator data for : Hospital characteristics for : Laboratory denominator information for : Number and proportion of invasive S. pneumoniae isolates penicillin-non-susceptible (PNSP), penicillin-resistant (PRSP), macrolide-non-susceptible (MNSP), single penicillin (PEN), single macrolides (MACR) and non-susceptible to penicillin and macrolides isolates, including 95 % confidence intervals (95 % CI), reported per country in : Distribution of single penicillin, single macrolides and non-susceptibility to penicillin and macrolides, among the most common serogroups reported per country in : Number and proportion of invasive S. aureus isolates resistant to meticillin (MRSA) and rifampin (RIF), including 95 % confidence intervals (95 % CI), reported per country in : Number of invasive E. faecalis and E. faecium isolates and proportion of high-level aminoglycoside-resistant E. faecalis and vancomycin-resistant E. faecium (%R), including 95 % confidence intervals (95 % CI), reported per country in : Number and proportion of invasive E. coli isolates resistant to aminopenicillins, third-generation cephalosporins, fluoroquinolones and aminoglycosides, and multiresistant (%R), including 95 % confidence intervals (95 % CI), reported per country in : Number of invasive E. coli isolates resistant to third-generation cephalosporins (CREC) and proportion of ESBL-positive (% ESBL) among these isolates, as ascertained by the participating laboratories in : Overall resistance and resistance combinations among invasive E. coli isolates tested against aminopenicillins, fluoroquinolones, third-generation cephalosporins and aminoglycosides (n = ) in Europe, : Number and proportion of invasive K. pneumoniae isolates resistant to fluoroquinolones, third-generation cephalosporins, aminoglycosides and multiresistant (%R), including 95 % confidence intervals (95 % CI), reported per country in a: Number and proportion of invasive K. pneumoniae isolates resistant to carbapenems and confidence intervals (95% CI) per country in : Number of invasive K. pneumoniae isolates resistant to third-generation cephalosporins (CRKP) and proportion ESBL-positive (% ESBL) among these isolates, as ascertained by the participating laboratories in : Overall resistance and resistance combinations among invasive K. pneumoniae isolates tested against fluoroquinolones, thirdgeneration cephalosporins and aminoglycosides (n = ) in Europe, : Number and proportion of invasive P. aeruginosa isolates resistant to piperacillin±tazobactam, fluoroquinolones, ceftazidime, aminoglycosides, carbapenems and multiresistant (%R), including 95 % confidence intervals (95 % CI), reported per country in : Overall resistance and resistance combinations among invasive Pseudomonas aeruginosa isolates tested against at least three antibiotic classes among piperacillin±tazobactam, ceftazidime, fluoroquinolones, aminoglycosides and carbapenems (n= 8 485) in Europe, List of figures 1.1: Organisation of EARS-Net : Percentage of EARS-Net participating laboratories employing interpretive criteria from various breakpoint committees for antimicrobial susceptibility testing in Only data for laboratories returning EQA data for K. pneumoniae and P. aeruginosa are included : Klebsiella pneumoniae: Percentage of invasive isolates resistant to carbapenems reported to EARSS/EARS-Net by year, (18 countries;140 laboratories) : Pseudomonas aeruginosa: Percentage of invasive isolates resistant to carbapenems reported to EARSS/EARS-Net by year, (18 countries;168 laboratories) : Number of participating laboratories returning reports, per country, iv

7 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe : Adherence to guidelines: number of laboratories per country, : Number of hospitals (A) and laboratories (B) reporting AMR and/or denominator data in : Proportion of small, medium and large hospitals per country, based on the number of beds, for all hospital reporting both antimicrobial resistance data and denominator data in : Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to penicillin (PNSP) in : Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to macrolides in : Streptococcus pneumoniae: proportion of invasive isolates with non-susceptibility to penicillin and macrolides in : Streptococcus pneumoniae: trends of non-susceptibility to penicillin by country, : Streptococcus pneumoniae: trends of non-susceptibility to macrolides by country, : Streptococcus pneumoniae: trends of non-susceptibility to penicillin and macrolides by country, : Distribution of serogroups and the resistance profile of S. pneumoniae isolates per serogroup in : Staphylococcus aureus: proportion of invasive isolates resistant to meticillin (MRSA) in : Staphylococcus aureus: trend of resistance to meticillin (MRSA) by country, : Enterococcus faecalis: proportion of invasive isolates with high-level resistance to aminoglycosides in : Enterococcus faecalis: trends of high-level resistance to aminoglycosides by country, : Enterococcus faecium: proportion of invasive isolates resistant to vancomycin in : Enterococcus faecium: trends of resistance to vancomycin by country : Escherichia coli: proportion of invasive isolates with resistance to third-generation cephalosporins in : Escherichia coli: proportion of invasive isolates with resistance to fluoroquinolones in : Escherichia coli: proportion of invasive isolates with resistance to aminoglycosides in : Escherichia coli: trends of resistance to aminopenicillin by country, : Escherichia coli: trends of resistance to third-generation cephalosporins by country, : Escherichia coli: trends of resistance to fluoroquinolones by country, : Escherichia coli: trends of resistance to aminoglycosides by country, : Escherichia coli: trends of combined resistance (resistant to fluoroquinolones, third-generation cephalosporins and aminoglycosides) by country, : Klebsiella pneumoniae: proportion of invasive isolates resistant to third-generation cephalosporins in : Klebsiella pneumoniae: proportion of invasive isolates resistant to fluoroquinolones in : Klebsiella pneumoniae: proportion of invasive isolates resistant to aminoglycosides in : Klebsiella pneumoniae: proportion of invasive isolates resistant to carbapenems in : Klebsiella pneumoniae: trends of resistance to third-generation cephalosporins by country, : Klebsiella pneumoniae: trends of resistance to fluoroquinolones by country, : Klebsiella pneumoniae: trends of resistance to aminoglycosides by country, : Klebsiella pneumoniae: trends of resistance to carbapenems by country, : Klebsiella pneumoniae: trend of multiresistance (third-generation cephalosporins, fluoroquinolones and aminoglycosides) by country, : Pseudomonas aeruginosa: proportion of invasive isolates resistant to piperacillin±tazobactam in : Pseudomonas aeruginosa: proportion of invasive isolates resistant to ceftazidime in : Pseudomonas aeruginosa: proportion of invasive isolates resistant to fluoroquinolones in : Pseudomonas aeruginosa: proportion of invasive isolates resistant to aminoglycosides in : Pseudomonas aeruginosa: proportion of invasive isolates resistant to carbapenems in : Pseudomonas aeruginosa: trend of resistance to piperacillin±tazobactam by country, : Pseudomonas aeruginosa: trend of resistance to ceftazidime by country, : Pseudomonas aeruginosa: trend of resistance to fluoroquinolones by country, : Pseudomonas aeruginosa: trend of resistance to aminoglycosides by country, : Pseudomonas aeruginosa: trend of resistance to carbapenems by country, : Pseudomonas aeruginosa: trend of combined resistance (R to three or more antimicrobial classes among piperacillin±tazobactam, ceftazidime, fluoroquinolones, aminoglycosides and carbapenems) by country, v

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9 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe 2010 Abbreviations and acronyms AMR Antimicrobial resistance MRSA Meticillin-resistant Staphylococcus aureus AmpC Ampicillinase C NDM New Delhi metallo-beta-lactamase AST Antimicrobial susceptibility testing NRL National reference laboratories BSAC British Society for Antimicrobial Chemotherapy NWGA Norwegian Working Group on Antimicrobials BSI Bloodstream infections OXA Oxacillinase gene CC Clonal complex PBP Penicillin-binding protein CLSI Clinical and Laboratory Standards Institute PCV Pneumococcal conjugate vaccine CMY CNSE CPE CREC CRG CRKP CSF DIN DNA EARSS EARS-Net ECDC EU EQA ESAC ESBL Cephamycinase Carbapenem-non-susceptible Enterobacteriaceae Carbapenemase-producing Enterobacteriaceae Third-generation cephalosporin-resistant Escherichia coli Commissie Richtlijnen Gevoeligheidsbepalingen (Dutch) Third-generation cephalosporin-resistant Klebsiella pneumoniae Cerebrospinal fluid Deutsche Industrie Norm (German) Deoxyribonucleic acid European Antimicrobial Resistance Surveillance System European Antimicrobial Resistance Surveillance Network European Centre for Disease Prevention and Control European Union External quality assessment European Surveillance of Antimicrobial Consumption Extended-spectrum beta-lactamase PNSP PRSP RNA SFM SIR SHV SRGA TESSy TEM UK NEQAS VISA VIM VRE WHO WHONET Penicillin-non-susceptible Streptococcus pneumoniae Penicillin-resistant Streptococcus pneumoniae Ribonucleic acid Comité de l Antibiogramme de la Société Française de Microbiologie (French) Sensitive, intermediate, resistant Sulfhydryl-variable extended-spectrum beta-lactamase gene Swedish Reference Group for Antibiotics The European Surveillance System (at ECDC) Temoneira extended-spectrum betalactamase gene United Kingdom National External Quality Assessment Scheme for Microbiology Vancomycin-intermediate Staphylococcus aureus Verona integron-encoded metallo-beta-lactamase Vancomycin-resistant enterococci World Health Organization WHO microbiology laboratory database software ESCMID European Society of Clinical Microbiology and Infectious Diseases ESGARS ESCMID Study Group for Antimicrobial Resistance Surveillance EUCAST European Committee on Antimicrobial Susceptibility Testing FREC Fluoroquinolone-resistant Escherichia coli ICU Intensive care unit IMP Imipenemase KPC Klebsiella pneumoniae carbapenemase MIC Minimum inhibitory concentration MLS Macrolide, lincosamide and streptogramin MNSP Macrolide non-susceptible Streptococcus pneumoniae vii

10 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT Countries participating in EARS-Net 2010 Participating countries Non participating countries IS FI NO SE EE IE DK LT LV UK BE NL DE PL LU CZ FR AT HU SI RO PT ES IT BG EL MT CY AT Austria FI Finland NL Netherlands BE Belgium FR France NO Norway BG Bulgaria HU Hungary PL Poland CY Cyprus IE Ireland PT Portugal CZ Czech Republic IS Iceland RO Romania DE Germany IT Italy SE Sweden DK Denmark LT Lithuania SI Slovenia EE Estonia LU Luxembourg UK United Kingdom EL Greece LV Latvia ES Spain MT Malta As of 1 January 2010, only EU and EEA Member States can report data to EARS-Net. Antimicrobial resistance surveillance data from five countries previously participating in EARSS (Bosnia-Herzegovina, Croatia, Israel, Switzerland and Turkey) are therefore not included in this report. viii

11 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe 2010 National institutions/organisations participating in EARS-Net Austria Federal Ministry of Health Medical University Vienna Elisabethinen Hospital, Linz Belgium Scientific Institute of Public Health University of Antwerp Bulgaria Alexander University Hospital, Sofia National Center of Infectious and Parasitic Diseases Cyprus Nicosia General Hospital Czech Republic National Institute of Public Health National Reference Laboratory for Antibiotics Denmark Statens Serum Institut, Danish Study Group for Antimicrobial Resistance Surveillance (DANRES) Estonia Health Board East-Tallinn Central Hospital Tartu University Hospital Finland National Institute for Health and Welfare, Finnish Hospital Infection Program (SIRO) Finnish Study Group for Antimicrobial Resistance (FiRe) France Pitié-Salpêtrière Hospital National Institute for Public Health Surveillance French National Observatory for the Epidemiology of Bacterial Resistance to Antimicrobials (ONERBA): Azay- Résistance, Île-de-France and Réussir networks National Reference Centre for Pneumococci (CNRP) Germany Robert Koch Institute Greece Hellenic Pasteur Institute National School of Public Health National and Kapodistrian University of Athens, Medical School Hungary National Centre for Epidemiology Ireland Health Protection Surveillance Centre (HPSC) Iceland National University Hospital of Iceland Centre for Health Security and Infectious Disease Control Italy National Institute of Public Health Latvia Paul Stradins Clinical University Hospital State Agency Infectology Centre of Latvia Lithuania National Public Health Surveillance Laboratory Institute of Hygiene Luxembourg National Health Laboratory Microbiology Laboratory, Luxembourg s Hospital Centre Malta Mater Dei Hospital, B Kara Netherlands National Institute for Public Health and the Environment Norway University Hospital of North Norway Norwegian Institute of Public Health St. Olav University Hospital, Trondheim Poland National Medicines Institute National Reference Centre for Antimicrobial Resistance and Surveillance ix

12 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT Portugal National Institute of Health Dr. Ricardo Jorge Ministry of Health Directorate-General of Health Romania National Institute of Research and Development for Microbiology and Immunology Cantacuzino Institute of Public Health Slovenia National Institute of Public Health University of Ljubljana Spain Health Institute Carlos lll National Centre of Microbiology Sweden Swedish Institute for Communicable Disease Control United Kingdom Health Protection Agency Health Protection Scotland Public Health Agency Northern Ireland x

13 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe 2010 Summary This report is based on antimicrobial resistance data reported to EARS-Net by 28 countries in 2010 and trend analyses including EARSS data from previous years. The data show that the Europe-wide increase of antimicrobial resistance observed in Escherichia coli during recent years is continuing unimpeded. The highest resistance proportions in E. coli were reported for aminopenicillins ranging up to 83 %. Despite the already high level of resistance the increase continues even in countries presenting resistance well above 50 %. The percentage of third-generation cephalosporin resistance reported among E. coli isolates has increased significantly over the last four years in half of the reporting countries, while a decreasing trend was observed in only one country. This resistance is directly linked to the high proportions ( %) of ESBL-positives among cephalosporin-resistant E. coli isolates reported in A high frequency of multi-drug resistant Klebsiella pneumoniae was observed in southern, central and eastern Europe. In half of the reporting countries, the proportion of multiresistant K. pneumoniae isolates (combined resistance to third-generation cephalosporins, fluoroquinolones and aminoglycosides) was above 10 % and five countries show an increasing trend of carbapenemresistant K. pneumoniae. Carbapenems have been widely used in many countries due to the increasing rate of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae with a consequent impact on the emergence of carbapenemase production (VIM, KPC and NDM-1). Other trends in the occurrence of resistance reported to EARS-Net bring hope that national efforts on infection control and efforts targeted at containment of resistance may in some cases bring the development of resistance to a halt, or even reverse undesirable resistance trends, as exemplified by the development for meticillin-resistant Staphylococcus aureus (MRSA). Even though the proportion of MRSA among S. aureus is still above 25 % in eight out of 28 countries, the occurrence of MRSA is stabilising or decreasing in some countries and a sustained decrease has been observed in Austria, Cyprus, Estonia, France, Greece, Ireland and the UK. Furthermore, the United Kingdom has shown a consistent reduction of resistant proportions in K. pneumoniae for all antimicrobial classes under surveillance, and in a few countries (Germany, Greece, Italy and the UK) the efforts to control glycopeptide resistance in Enterococcus faecium seem to be successful and resulting in a continuous decrease of proportions of resistant isolates. Meanwhile, high-level aminoglycoside resistance in Enterococcus faecalis is stabilising in Europe at a level of %. For Streptococcus pneumoniae, non-susceptibility to penicillin remains generally stable in Europe and non-susceptibility to macrolides has declined in five countries while an increasing trend was observed in only one country. For Pseudomonas aeruginosa, high proportions of resistance to fluoroquinolones, carbapenems and combined resistance have been reported by many countries, especially in southern and eastern Europe. For several antimicrobial and pathogen combinations, e.g. fluoroquinolone resistance in E. coli, K. pneumoniae, P. aeruginosa and for MRSA, a north to south gradient is evident in Europe. In general, lower resistance proportions are reported in the north and higher proportions in the south of Europe. This is likely to be a reflection of differences in infection control practices, presence or absence of legislation regarding prescription of antimicrobial drugs. However, for K. pneumoniae, increasing trends of resistance to specific antimicrobial classes and of multiresistance have also been observed in northern European countries, like Denmark and Norway, which traditionally have a prudent approach to antimicrobial use. In addition to the regular trend analysis and situation overview, this 2010 EARS-Net report contains a focus chapter providing in-depth analysis for carbapenemresistant K. pneumoniae and P. aeruginosa. Results from susceptibility testing to carbapenems for these two pathogens reported since 2005, reveal a significant decrease of susceptibility to carbapenems in invasive K. pneumoniae over the period Carbapenems are some of the few effective antimicrobials for the treatment of infections caused by bacteria that produce extended-spectrum beta-lactamases and thus resistance to carbapenems leaves very few therapeutic options available. Based on EARS-Net data, the antimicrobial resistance situation in Europe displays large variation depending on pathogen type, antimicrobial substance and geographical region. Besides evidence of stabilisation of the situation for some pathogens (e.g. MRSA) in a number of countries, the data show the unimpeded decline of antimicrobial susceptibility in other major pathogens (e.g. E. coli) and the alarming emergence of carbapenem resistance in K. pneumonia, leading to an unfortunate loss of antimicrobial treatment options. 1

14 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT Figure 1.1: Organisation of EARS-Net National Laboratories National Epidemiological Contact Points Disease Experts Data Managers National Advisory Board EUCAST ESCMID ESAC-Net HAI-Net European Antimicrobial Resistance Surveillance Network (EARS-Net) at European Centre for Disease Prevention and Control (ECDC) EARS-Net Coordination Group WHO 2

15 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe Introduction This is the second Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS- Net) published by European Centre of Disease Prevention and Control (ECDC). The report represents the continuation of a series of highly valued EARSS Annual Reports published by the network since The results presented in this report are based on data submitted from over 900 laboratories serving more than 1400 hospitals in 26 EU Member States, Norway and Iceland. Surveillance of antimicrobial resistance within the EU is carried out in agreement with Decision No 2119/98/ EC of the European Parliament and of the Council of 24 September 1998 and Regulation (EC) No 851/2004 of the European Parliament and of the Council of 21 April 2004 establishing a European Centre for Disease Prevention and Control. The antimicrobial resistance surveillance data collected previously by EARSS and currently by EARS-Net, play an important role in documenting the occurrence and spread of antimicrobial resistance in Europe, and contribute to raising awareness of the problem at the political level, among public health officials, in the scientific community and in the general public. In the present report, results referring to 2010 and trend analyses including data from previous years are presented and discussed in Chapter 5. This year s focus chapter (Chapter 2) is on carbapenem-resistant K. pneumoniae and P. aeruginosa. Country-specific information is provided in Annex 2. About EARS-Net The European Antimicrobial Resistance Surveillance Network (EARS-Net) is a European-wide network of national surveillance systems, providing European reference data on the occurrence of antimicrobial resistance. EARS-Net is the largest publicly funded surveillance system for antimicrobial resistance in Europe. The management and coordination of EARS-Net was transferred from the Dutch National Institute for Public Health and the Environment (RIVM) to the European Centre for Disease Prevention and Control in January At ECDC, the management and coordination of EARS-Net is carried out by the Surveillance Section in collaboration with the Disease Programme for Antimicrobial Resistance and Healthcare-associated Infections. Scientific guidance and support to the coordination of the network is provided by the EARS-Net Coordination Group (see Figure 1.1), composed of experts selected from among the nominated disease-specific contact points and experts from other organisations involved in surveillance of antimicrobial resistance. EARS-Net activities are coordinated in close collaboration with two other major surveillance networks: the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) and the Healthcare-associated Infections Surveillance Network (HAI-Net). EARS-Net collaborates with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), in particular with the society s subcommittee, the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Data for EARS-Net are provided by a network of national surveillance systems in the participating countries. The national surveillance systems collect data from clinical laboratories on antimicrobial susceptibility of seven bacterial pathogens of public health importance in humans: Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae and Pseudomonas aeruginosa. The majority of countries participating in EARS-Net even collect and report denominator data on laboratory/hospital activity and patient characteristics. The data from national surveillance systems are uploaded by national data managers to a central database at ECDC (The European Surveillance System, TESSy ). After uploading, each country approves its own data and the results are made available from the ECDC website. EARS-Net maintains an interactive database at the ECDC website i and publishes annual reports on the occurrence of antimicrobial resistance in Europe. i index.aspx 3

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17 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe Carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa Analysis of data from laboratories reporting continuously from 2005 to Introduction The increase of carbapenem resistance in Gram-negative bacteria has become an exceedingly important clinical and public health issue in recent years. Carbapenems are some of the few effective antimicrobials for the treatment of infections caused by bacteria that produce extended-spectrum beta-lactamases and so resistance to carbapenems leaves very few therapeutic options 1. Although carbapenem resistance in both Klebsiella pneumoniae and Pseudomonas aeruginosa can result through various mechanisms of resistance 2, the emergence and spread of carbapenemases, a group of clinically important beta-lactamases, especially in members of Enterobacteriaceae family 1 4, has made the surveillance of carbapenem resistance and carbapenemases in Gram-negative bacteria imperative. Key points A significant decrease in susceptibility to carbapenems in invasive K. pneumoniae isolates was observed in Europe from 2005 to During the same period, no significant change in susceptibility to carbapenems in invasive P. aeruginosa isolates was observed. A marked heterogeneity was observed with regard to the interpretive criteria being used by clinical microbiology laboratories for reporting susceptibility testing results. Harmonised use of breakpoints would substantially increase the comparability of data. Carbapenem resistance can result through various mechanisms, including the production of carbapenemases. Confirming the presence of carbapenemases in Enterobacteriaceae, would allow a closer surveillance of the spread of carbapenemase-producing Enterobacteriaceae (CPE) in Europe. Carbapenemase enzymes that can efficiently hydrolyse most beta-lactams, including carbapenems 1,3 have emerged and spread among all members of the Enterobacteriaceae family worldwide 4 6. Though the exact prevalence of carbapenemase-producing Enterobacteriaceae (CPE) in healthcare facilities and in the community in Europe is not known, publications from Member States indicate that CPE are endemic in certain countries in Europe 7,8. Although some of the most widespread types of carbapenemases found in Enterobacteriaceae are K. pneumoniae carbapenemase (KPC) and Verona integron-encoded metallo-beta-lactamase (VIM) 8 13, other carbapenemases like OXA-48 9,14 and New Delhi metallo-beta-lactamase (NDM) 15,16 have also emerged. Variants of NDM carbapenemase, such as NDM-2, have recently been reported from countries in the north of Africa 17. The emergence and spread of CPE has been identified as a public health threat, especially since recent studies on CPE 18,19 and carbapenem-non-susceptible Enterobacteriaceae (CNSE) 20,21 have shown that infection or colonisation is associated with higher in-hospital mortality. Results from testing the susceptibility of K. pneumoniae and P. aeruginosa to carbapenems have been reported to EARSS/EARS-Net by participating clinical microbiological laboratories since Susceptibility to carbapenems reported to EARS-Net is based on the results of testing against either imipenem or meropenem. The choice of which breakpoint committee s interpretive criteria is used for the interpretation of minimum inhibitory concentrations (MIC) as either susceptible (S), intermediate (I) or resistant (R), is at the discretion of each clinical microbiology laboratory. In general, however, EARS-Net encourages the use of EUCAST breakpoints. Because of the public health impact of infections caused by CPE, it is important to follow the trends of carbapenem resistance in Europe. Confirming the presence of carbapenemases in bacteria and understanding the extent of the reservoir in Europe is a prerequisite for targeted intervention to control the spread. Although carbapenem susceptibility results are available from EARS-Net reports, it is important to note that these only provide resistance profiles with no further characterisation of resistance mechanisms. The results may therefore be useful for the surveillance of carbapenem resistance in Gram-negative bacteria, but may not be useful for following the occurrence of carbapenemases. Performance of phenotypic and molecular testing for screening and confirmation of the presence of carbapenemases would add a significant and important layer of information to the existing data. 5

18 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT 2.2 Methods Results of testing susceptibility to carbapenems of invasive K. pneumoniae and P. aeruginosa isolates causing blood stream infections (BSI) and infections of cerebrospinal fluid (CSF) were extracted from the EARSS/EARS-Net database for A trend analysis was performed using the Cochran-Armitage test for trend for both K. pneumoniae and P. aeruginosa. The following data were also extracted from the EARSS/ EARS-Net database with regard to reporting of carbapenem resistance of K. pneumoniae and P. aeruginosa isolates from 2005 to 2010: the number of countries reporting to EARSS/EARS-Net annually for these organisms, the number of clinical microbiology laboratories reporting to EARSS/EARS-Net per country per year, the number of clinical microbiology laboratories in each country that have reported their results continuously during the period (some countries may report through one central laboratory), the total number of laboratories using the interpretive criteria of various breakpoint committees as reported by EARS-Net laboratories participating in the 2010 EARS-Net External Quality Assessment (EQA) exercise (see Figure 3.2). 2.3 Results Number of participating countries Twenty-one countries reported results to EARSS for K. pneumoniae and 22 reported for P. aeruginosa, in 2005; this number had increased to 28 for both organisms by Eighteen countries reported continuously for the two pathogens throughout the period Trend Figure 2.1: Percentage of EARS-Net participating laboratories employing interpretive criteria from various breakpoint committees for antimicrobial susceptibility testing in Only data for laboratories returning EQA data for K. pneumoniae and P. aeruginosa are included % labs particpating BSAC COMB CLSI CRG DIN EUCAST NWGA SFM SRGA Other Data: UKNEQAS 2010 BSAC: British Society of Antimicrobial Chemotherapy; COMB: Combination; CLSI: Clinical Laboratory Standards Institute; CRG: Commissie Richtlijnen Gevoeligheidsbepalingen; DIN: Deutsches Institut für Normung; EUCAST: European Committee for Antimicrobial Susceptibility Testing; NWGA: Norwegian Working Group on Antibiotics; SFM: Société Française de Microbiologie; SRGA: Swedish Reference Group for Antibiotics. Figure 2.2: Klebsiella pneumoniae: Percentage of carbapenem-resistant invasive isolates reported to EARSS/EARS-Net by year, (18 countries; 140 laboratories) 20 Percentage Only laboratories that continuously reported susceptibility results for carbapenems during the period are included in the analysis. 6

19 SURVEILLANCE REPORT Antimicrobial resistance surveillance in Europe 2010 analyses for presented in this chapter for both K. pneumoniae and P. aeruginosa are based only on data from the laboratories reporting continuously during the period (Table 2.1). Participation of clinical microbiology laboratories There has been an overall increase of 56 % (366 to 570) and 69 % (312 to 526) in the total numbers of clinical microbiology laboratories reporting K. pneumoniae and P. aeruginosa isolates, respectively, from 2005 to Number of continuously reporting laboratories The numbers of laboratories continuously reporting susceptibility results for K. pneumoniae and P. aeruginosa isolates throughout the period , were 140 and 168, respectively. The number of continuously reporting laboratories per country and the average number of isolates per year and country can be seen in Table 2.1. Use of various interpretive criteria by participating laboratories The distribution of the interpretive criteria used by all laboratories that participated in the EARS-Net EQA in June 2010 is shown in Figure 2.1. Data from this EQA showed that 66 % of participating laboratories used guidelines from the Clinical Laboratory Standards Institute (CLSI) and 14 % used those from the European Committee on Antimicrobial Susceptibility Testing (EUCAST); making the interpretive criteria provided by these the two breakpoint committees the most widely used. Trends in resistance Klebsiella pneumoniae Between 2005 and 2010, a total of 140 laboratories from 18 countries continuously reported results on the susceptibility to carbapenems of invasive K. pneumoniae isolates. During this period, the number of laboratories reporting continuously per country ranged from one laboratory in the Czech Republic, Iceland, Malta and Sweden, to 33 laboratories in France. Trend analysis was performed only on the results from these 140 laboratories. Results from this analysis show that in Europe the proportion of K. pneumoniae isolates resistant to carbapenems increased from 8 % to 15 % between 2005 and This increase was found to be highly significant (p < 0.001) (Figure 2.2) but this is mainly due to a substantial increase in a few countries. For more detailed trends of carbapenem resistance in K. pneumoniae per country for , please refer to chapter 5, figure Pseudomonas aeruginosa A total of 168 laboratories from 18 countries continuously reported results on susceptibility of invasive P. aeruginosa isolates to carbapenems between 2005 and The number of laboratories continuously reporting per country, ranged from one each in Bulgaria, Iceland and Malta to 24 in Greece. Trend analysis was performed only on the results from these 168 laboratories. Results from this analysis show that in Europe the proportion of P. aeruginosa isolates resistant to carbapenems was 22 % in 2005, increased to 24 % in 2008, and decreased to 22 % in Trend analysis on these data showed no significant change over the study period (p < 0.49) (Figure 2.3). For more detailed trends of carbapenem resistance in P. aeruginosa per country for , please refer to chapter 5, figure Discussion Results from the analyses in this report show that carbapenem resistance is significantly increasing among K. pneumoniae invasive isolates in Europe. Reports from Figure 2.3: Pseudomonas aeruginosa: Percentage of carbapenem-resistant invasive isolates reported to EARSS/EARS- Net by year, (18 countries; 168 laboratories) Percentage Only laboratories that continuously reported susceptibility results for carbapenems during the period are included in the analysis. 7

20 Antimicrobial resistance surveillance in Europe 2010 SURVEILLANCE REPORT Member States showing similar susceptibility results and an increasing number of reports documenting the spread of CPE have given rise to the suspicion that susceptibility of Enterobacteriaceae to carbapenems is decreasing across Europe. The proportion of carbapenem-resistant P. aeruginosa, which is already high at 22 %, showed no significant increase. The increase in resistance to carbapenems in K. pneumoniae, as well as the high level of resistance in P. aeruginosa, constitutes a serious public health concern, since few therapeutic options are available for the treatment of carbapenemresistant infections. When making inferences based on the available data on carbapenem-resistant P. aeruginosa and K. pneumoniae, a number of limitations regarding detection and testing should be taken into consideration. One of the difficulties of accurately detecting carbapenem resistance is that it may be the result of a variety of mechanisms of resistance, including the presence of outer membrane porin protein loss, increased activity of efflux pumps, the production of extended-spectrum betalactamases or AmpC beta-lactamases in combination with porin loss and last, but not least, the production of carbapenemases 2,8. Furthermore, even with routine antimicrobial susceptibility testing, CPE can demonstrate significant variation in their carbapenem MICs, even falling within the susceptibility range as defined by either the CLSI 22 or EUCAST 23, despite a recent reduction of the susceptibility breakpoints for carbapenems and Enterobacteriaceae by CLSI 24. Moreover, certain testing methods, such as automatic testing, have been shown to not always distinguish between Enterobacteriaceae that produce carbapenemases and those that carry other mechanisms of resistance (e.g. ESBLs and/or porin loss) 8,25. Another issue affecting the comparability of susceptibility testing results is the marked heterogeneity of the breakpoints used by laboratories in Europe. As shown in Figure 2.1, the most commonly used breakpoints are those from CLSI, followed by EUCAST, but interpretive criteria from a number of other committees are also followed. While the effect of this heterogeneity on the susceptibility results and trends presented here are not explored, it can be argued that in order to obtain fully comparable results, harmonisation of the use of breakpoints and interpretive criteria for all reporting laboratories is needed. The increased morbidity, mortality and overall public health impact of infections with carbapenemase-producing bacteria calls for action to prevent the spread of these bacteria and resistance mechanisms in Europe. Data on carbapenem resistant bacteria is available through existing surveillance systems; however, in the absence of data on the mechanisms of resistance in these bacteria, the real prevalence of carbapenemaseproducing bacteria remains unknown. Having this information would provide better understanding of the extent of the reservoir in Europe, which is a prerequisite for designing and implementing targeted interventions to control the spread. In support of this, a recent ECDC risk assessment on the spread of CPE through patient transfer between healthcare facilities, with special emphasis on cross-border transfer 6 suggests that the elements necessary to curb the spread of CPE include surveillance data, prompt detection of carbapenem resistance in Enterobacteriaceae, and confirmation of the production of carbapenemases in these bacteria 6,8. Table 2.1: Numbers of laboratories reporting continuously and average numbers of K. pneumoniae and P. aeruginosa isolates reported per country per year to EARSS/EARS-Net during Country K. pneumoniae P. aeruginosa Number of laboratories* Average number of isolates per year Number of laboratories* Average number of isolates per year Austria Bulgaria Cyprus Czech Republic Estonia Finland France Greece Hungary Iceland Ireland Malta Netherlands Norway Slovenia Spain Sweden United Kingdom Total * In some countries, data from several laboratories may be reported to EARS-Net from one central laboratory. 8